Despite multimodal treatments, such as radiation therapy, malignant gliomas (MG) are rapidly fatal. Resistance of MG to radiation therapy (RT) is a consequence of both intrinsic cancer cell properties and protective influence of the tumor microenvironment. We previously demonstrated that RT-induced cell death causes the release of danger signals recruiting Toll-like Receptor-9 (TLR9)-positive myeloid cells which jump-start tumor vascularization and regrowth. The proangiogenic (rather than immunostimulatory) effects of TLR9 activation are mediated by NF-?B/IL-6-dependent activation of Signal Transducer and Activator of Transcription (STAT3). STAT3 is a multifaceted oncogene and a central immune checkpoint regulator activated in cancer cells and in tumor-associated myeloid cells in patients with MG and with other tumors. It remains an elusive target, with no FDA-approved direct small molecule STAT3 inhibitors. To overcome this challenge, we previously developed a strategy to deliver STAT3 siRNA specifically into TLR9-positive myeloid cells and glioma cells, by physically linking siRNA to TLR9 ligands, CpG oligodeoxynucleotides (ODNs). Our previous preclinical studies demonstrated that local tumor treatment using CpG-STAT3siRNA silences STAT3 in glioma and other tumor models, thereby reducing tumor revascularization while stimulating systemic antitumor immunity. We propose to use a new generation of CpG-STAT3 inhibitors (CSIs) based on STAT3 antisense oligonucleotide (CpG- STAT3ASO) or STAT3 decoy oligodeoxynucleotide (CpG-STAT3dODN) design to support RT against recurrent human MG. We propose studies to assess feasibility, pharmacokinetic/pharmacodynamic properties, efficacy and safety of systemic administration of new CSIs against human and mouse models of MG in vivo. Our aim is to produce clinically relevant, effective and safe CSI-based strategies capable of overcoming RT resistance in MG in order to generate long term antitumor immune responses.